Monoclonal antibodies and monoclonal antibody fragments will be labeled with the beta-emitting radionuclide, yttrium-90 (90Y, T 1/2 = 64.- hr), and studied preclinically to assess their potential as agents for radioimmuntherapy of cancer. Bifunctional chelate techniques which will give enhanced in vivo stability will be developed in order to circumvent the high bone and reticuloendothelial uptakes and consequent dose-limiting bone marrow toxicity associated with currently available methods for production of 90Y-labeled monoclonal antibodies. Monoclonal antibody CO17-1A, which has specificity for colorectal and pancreatic carcinomas, will be chelate conjugated using the new bifunctional chelate techniques. Radioimmunoassay will be used to monitor retention of immunoreactivity following conjugation. Tissue distribution studies of 90Y-labeled CO17-1A in athymic nude mice bearing xenografts of human colorectal carcinoma cell line SW 948 will permit assessment of the potential of the new bifunctional chelate techniques. Control studies will be used to evaluate the importance of nonspecific binding. Absorbed radiation dose calculations will enable selection of tumoricidal dosages of 90Y-labeled CO17-1A for use in tumor growth/regression studies in nude mice bearing tumor xenografts. Calcium DTPA encapsulated in large unilamella vesicle (LUV) liposomes will be evaluated for decorporation of the 90Y which becomes dissociated in vivo from 90Y-labeled CO17-1A via either catabolism or "leakage." Use of the radioprotective drug, WR- 2721, as an adjunct to 90Y-labeled monoclonal antibody therapy for reducing the radiation dose to the bone marrow will be studied. WR-2721 will also be coupled to monoconal antibody 16B-13, which has specificity for the bone marrow, in order to direct the radioprotective effect more specifically to that organ. The research will be extended to other monoclonal antibodies against gastrointestinal tumors (BR55-2 and 1116-NS-19-9) and melanoma (ME-361 and 691-19-19), as well as Fab and F(ab')2 fragments of monoclonal antibodies. This multidiscplinary research approach, which combines the fields of bio-organic chemistry, immunochemistry, and radiopharmacology, is aimed at development of improved methods for radioimmunotherapy of cancer in man.